While ADH plays a central role in the renal concentrating mechanism, several situations have been described wherein hyperosmotic urine was produced in the absence of ADH. We have recently shown that dehydration of DI rats for 24h elevates urine osmolality to almost 700 mosmol/kg. While this response was accompanied by a fall in GFR, other studies with aortic constriction in DI rats showed that such a fall was not essential for increased concentrating ability. These studies utilized our chronic rat preparation with chronically implanted catheters in the carotid artery, jugular and renal veins, and urinary bladder. The goal of the proposed studies is to utilize similar clearance procedures in conscious DI rats to study the following aspects of the concentrating mechanism during deydration: (1) To quantify the magnitude and time course of changes in GFR, RPF, FEurea, FENa, CH2O, etc. in relation to UOsm. The changes in renal tubular events in the same rats will then be examined by micropuncture several days later; (2) To seek, by freeze-fracture, any changes in collecting duct cell membrane topography that might reflect altered water permeability (in the absence of ADH). In this regard, the potential role of endogenous oxytocin will be examined; (3) To quantify the magnitude and time course of changes in the corticopapillary gradient, to identify the major solutes involved, and to determine the extent of osmotic equilibration (4) To determine, by use of specific blockers, the ADH-independent roles of the renin-angiotensin, prostaglandin, and adrenergic systems in the concentrating mechanism of normally-hydrated and dehydrated DI rats; (5) These experiments will be repeated in separate series of DI rats in which ADH is replaced to physiological levels. The influence of ADH on these other systems will thus be determined. In addition to identifying non-ADH-dependent mechanisms of urine concentration, we seek to determine their relative importance versus time, and the nature of their interrelationship and interdependence, if any. It is possible that some of these mechanisms may account for the hyponatremia of such clinical conditions as heart and liver failure.